The present invention relates to a rapidly disintegrating pharmaceutical composition for sublingual administration of fentanyl, to a method for the treatment of acute pain and to a method of manufacture of a corresponding medicament.
Acute and/or severe pain is a common cause of emergency treatment or hospitalization. In cancer patients, pain is usually treated with non-steroid anti-inflammatory drugs (NSAIDs) and opiates alone or in combination. Opioid-requiring cancer pain patients are usually given slow-release opiates (slow-release morphine or ketobemidone or transdermal fentanyl). A characteristic feature of cancer pain are periods of inadequate analgesia (breakthrough pain) Most often they are due to increased physical activity of the patient. However, treatment of breakthrough pain by administration of increased time contingent doses of long-acting analgesics causes adverse side effects such an excess sedation, nausea, and constipation. Presently available oral, rectal, or sublingual analgesic formulations have relatively lengthy onset times or erratic absorption characteristics that are not well suited to control acute or breakthrough pain.
Conditions of acute operative/postoperative or traumatic/posttraumatic pain as well as pain due to severe disease (e.g. myocardial infarction, nephrolithiasis, etc.) is usually treated with opioid analgesics which are administered parenterally (by intravenous or intramuscular administration) to obtain a rapid onset of analgesia. In such cases, rapid-onset oral alternatives are of considerable therapeutic interest.
Fentanyl, N-(1-phenethyl-4-piperidyl)-propioanilide, is an opioid agonist and shares many of the pharmacodynamic effects of opiates such as morphine and meperidine. However, compared to these opiates, fentanyl exhibits little hypnotic activity, rarely induces histamine release, and respiratory depression is more short-lived. Fentanyl is commercially available for intravenous, intrabuccal (lozenge-transmucosal) and transdermal administration.
Following parenteral administration of fentanyl, the analgesic action is more prompt and less prolonged than that of morphine and meperidine. The onset of analgesia following i.v. administration is rapid. Peak analgesia is obtained within a few minutes. Following transbuccal administration by a lozenge, consumption of the lozenge is usually complete within 30 min and peak plasma concentrations appear around 20 minutes, as described by e.g. Farrar et al. J. Natl. Cancer Inst. 1998, 90(8), p. 611-616, Analgesia is apparent within 5-15 min and peaks at about 20-50 min. While this is an improvement over oral administration for gastrointestinal uptake, a quicker onset of analgesia would be of substantial benefit to the patient. In addition, substantial amounts of lozenge-administered fentanyl are swallowed by the patient. This is not desirable and results in the administration of excessive amounts of the drug, which may give rise to side effects.
Fentanyl shares the toxic potential of opiate agonists, and the usual precautions in this field must be observed. Respiratory depression is the most serious adverse event, occurring after bucchal, parenteral as well as transdermal administration. In patients receiving transmucosal fentanyl, facial flushing and pruritus is relatively common. Nausea and vomiting are also frequent after bucchal therapy.
It is one object of the invention to provide for the treatment of acute or breakthrough pain by perorally administering fentanyl in a manner giving rise to pharmacologically effective plasma levels of fentanyl within a short time after administration.
It is another object of the invention to provide a pharmaceutical composition suitable for that purpose.
It is a further object of the invention to provide a method of making such a composition.
It is an additional object of the invention to provide a method of manufacture of a medicament for sublingual administration containing a physiologically effective dose of fentanyl useful in the treatment of acute pain.